Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhood

Neuronal ceroid lipofuscinoses (NCLs) are the most common hereditary neurod egenerative diseases of childhood. The infantile form, INCL, is caused by l ysosomal palmitoyl-protein thioesterase (PPT) deficiency, which impairs the cleavage of thioester linkages in palmitoylated proteins, preventing their hydrolysis by lysosomal proteinases. Consequent accumulation of these lipi d-modified proteins (constituents of ceroid) in lysosomes leads to INCL. Be cause thioester linkages are susceptible to nucleophilic attack, drugs with this property may have therapeutic potential for INCL. We report here that two such drugs, phosphocysteamine and N-acetylcystelne, disrupt thioester linkages in a model thioester compound, [C-14]palmitoyl-CoA. Most important ly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel p harmacological approach to lysosomal ceroid depletion and raise the possibi lity that nucleophilic drugs such as phosphocysteamine hold therapeutic pot ential for INCL.